Search

Purpose: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA)., Methods: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status., Results: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT , FGFR2 , IDH1 , and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input., Conclusion: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care., Competing Interests: Karthikeyan Murugesan Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Pharma AG Patents, Royalties, Other Intellectual Property: Antibiotic resistance causation identification (US10629291B2) filed with Koninklijke Philips NV, Analytic prediction of antibiotic susceptibility (US20190279738A1) filed with Koninklijke Philips NV, Methods and devices for characterizing and treating combined hepatocellular cholangiocarcinoma, with Foundation Medicine Inc Travel, Accommodations, Expenses: Foundation Medicine Radwa Sharaf Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Meagan Montesion Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jay A. Moore Employment: Foundation Medicine Stock and Other Ownership Interests: Roche James Pao Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Provisional patent submitted for Foundation Medicine, dealing with machine learning for gene predictions Dean C. Pavlick Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Vivek A. Upadhyay Employment: EQRx Stock and Other Ownership Interests: EQRx Consulting or Advisory Role: Foundation Medicine Brian M. Alexander Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Lilly, Puma Biotechnology, Celgene Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summary Vincent A. Miller Employment: Foundation Medicine, EQRx Leadership: Revolution Medicines Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics, Revolution Medicines, EQRx Patents, Royalties, Other Intellectual Property: Receives periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Milind M. Javle Consulting or Advisory Role: QED Therapeutics, Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono Other Relationship: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer Tanios S. Bekaii Saab Consulting or Advisory Role: Amgen, Ipsen, Lilly, Bayer, Roche/Genentech, AbbVie, Incyte, Immuneering, Seattle Genetics, Pfizer, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation Medicine Patents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687 Other Relationship: Exelixis, Merck, AstraZeneca, Lilly, Pancreatic Cancer Action Network Lee A. Albacker Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics, Tango Therapeutics Research Funding: Foundation Medicine Siraj M. Ali Employment: EQRx Consulting or Advisory Role: Elevation Oncology, In8bio, Pillar Biosciences, Takeda, ArcherDx Stock and Other Ownership Interests: In8bio, Pillar Biosciences, EQRx Patents: Foundation Medicine No other potential conflicts of interest were reported. Karthikeyan Murugesan Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Pharma AG Patents, Royalties, Other Intellectual Property: Antibiotic resistance causation identification (US10629291B2) filed with Koninklijke Philips NV, Analytic prediction of antibiotic susceptibility (US20190279738A1) filed with Koninklijke Philips NV, Methods and devices for characterizing and treating combined hepatocellular cholangiocarcinoma, with Foundation Medicine Inc Travel, Accommodations, Expenses: Foundation Medicine Radwa Sharaf Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Meagan Montesion Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jay A. Moore Employment: Foundation Medicine Stock and Other Ownership Interests: Roche James Pao Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Provisional patent submitted for Foundation Medicine, dealing with machine learning for gene predictions Dean C. Pavlick Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Vivek A. Upadhyay Employment: EQRx Stock and Other Ownership Interests: EQRx Consulting or Advisory Role: Foundation Medicine Brian M. Alexander Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Lilly, Puma Biotechnology, Celgene Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summary Vincent A. Miller Employment: Foundation Medicine, EQRx Leadership: Revolution Medicines Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics, Revolution Medicines, EQRx Patents, Royalties, Other Intellectual Property: Receives periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Milind M. Javle Consulting or Advisory Role: QED Therapeutics, Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono Other Relationship: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer Tanios S. Bekaii Saab Consulting or Advisory Role: Amgen, Ipsen, Lilly, Bayer, Roche/Genentech, AbbVie, Incyte, Immuneering, Seattle Genetics, Pfizer, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation Medicine Patents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687 Other Relationship: Exelixis, Merck, AstraZeneca, Lilly, Pancreatic Cancer Action Network Lee A. Albacker Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics, Tango Therapeutics Research Funding: Foundation Medicine Siraj M. Ali Employment: EQRx Consulting or Advisory Role: Elevation Oncology, In8bio, Pillar Biosciences, Takeda, ArcherDx Stock and Other Ownership Interests: In8bio, Pillar Biosciences, EQRx Patents: Foundation Medicine No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A , and CDKN2B , and has been correlated with worsened outcomes and immunotherapy resistance. MTAP -loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP- loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. Materials and Methods We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP- loss and MTAP- intact tumors in a retrospective study. Results The prevalence of MTAP -loss in GI cancers is 8.30%. MTAP -loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP -loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P  = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P  = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM , BRAF , BRCA2 , ERBB2 , IDH1 , PIK3CA , and PTEN) were observed in MTAP -loss tumors and varied according to tumor type. MTAP -loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP -loss versus MTAP -intact IHCC tumors (23.2% vs 31.2%, P  = .017). Conclusion In GI cancers, MTAP -loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP -loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations. [ABSTRACT FROM AUTHOR]